Complexity-Building ESIPT-Assisted Synthesis of Fused Polyheterocyclic Sulfonamides

Excited State Intramolecular Proton Transfer (ESIPT), originally discovered and explored in depth in a number of extensive photophysical studies, is more recently rediscovered as a powerful synthetic tool, offering rapid access to complex polyheterocycles. In our prior work we have employed ESIPT in aromatic o-keto amines and amides, leading to diverse primary photoproducts—complex quinolinols or azacanes possessing a fused lactam moiety—which could additionally be modified in short, high-yielding postphotochemical reactions to further grow complexity of the heterocyclic core scaffold and/or to decorate it with additional functional groups. Given that sulfonamides are generally known as privileged substructures, in this study we pursued two goals: (i) To explore whether sulfonamides could behave as proton donors in the context of ESIPT-initiated photoinduced reactions; (ii) To assess the scope of subsequent complexity-building photochemical and postphotochemical steps, which give access to polyheterocyclic molecular cores with fused cyclic sulfonamide moieties. In this work we show that this is indeed the case. Simple sulfonamide-containing photoprecursors produced the sought-after heterocyclic products in experimentally simple photochemical reactions accompanied by significant step-normalized complexity increases as corroborated by the Böttcher complexity scores.

Given that the sulfonamide moiety is prominently featured in approved drugs and other biologically active compounds [12][13][14][15][16][17][18][19], in this study we set out to explore ESIPT in sulfonamides and assess its synthetic utility.As noted above, another aspect of this work was to evaluate the compatibility of this molecular complexity-building photoassisted synthetic chemistry approach with fundamental principles of combinatorial chemistry and diversity-oriented synthesis [6].This includes the mutually interrelated goals of: (i) Modular design of photoprecursors from readily available building blocks (ii) Incursions into the unexplored areas of chemical space, especially via diversification of the core polyheterocyclic scaffolds.Given that the sulfonamide moiety is prominently featured in approved drugs and other biologically active compounds [12][13][14][15][16][17][18][19], in this study we set out to explore ESIPT in sulfonamides and assess its synthetic utility.As noted above, another aspect of this work was to evaluate the compatibility of this molecular complexity-building photoassisted synthetic chemistry approach with fundamental principles of combinatorial chemistry and diversity-oriented synthesis [6].This includes the mutually interrelated goals of: (i) Modular design of photoprecursors from readily available building blocks (ii) Incursions into the unexplored areas of chemical space, especially via diversification of the core polyheterocyclic scaffolds.

Results
Photoprecursor sulfonamides were readily synthesized in a modular fashion as shown in Scheme 2. Well-established high yielding reactions were chosen to link the building blocks together, i.e., the likes of Suzuki coupling or effective coupling of aromatic amines with sulfonyl chlorides.Generally, three diversity inputs (the photoactive core, i.e., aminoketone, the sulfonamide tether, and the unsaturated pendant) allow for added flexibility in exploring the chemical space traversed by the resulting photoproducts.Subsequent postphotochemical modifications offer opportunities for additional diversity inputs.

Results
Photoprecursor sulfonamides were readily synthesized in a modular fashion as shown in Scheme 2. Well-established high yielding reactions were chosen to link the building blocks together, i.e., the likes of Suzuki coupling or effective coupling of aromatic amines with sulfonyl chlorides.Generally, three diversity inputs (the photoactive core, i.e., aminoketone, the sulfonamide tether, and the unsaturated pendant) allow for added flexibility in exploring the chemical space traversed by the resulting photoproducts.Subsequent postphotochemical modifications offer opportunities for additional diversity inputs.Scheme 1. Synthetic utilization of ESIPT-generated azaxylylenes.
Given that the sulfonamide moiety is prominently featured in approved drugs and other biologically active compounds [12][13][14][15][16][17][18][19], in this study we set out to explore ESIPT in sulfonamides and assess its synthetic utility.As noted above, another aspect of this work was to evaluate the compatibility of this molecular complexity-building photoassisted synthetic chemistry approach with fundamental principles of combinatorial chemistry and diversity-oriented synthesis [6].This includes the mutually interrelated goals of: (i) Modular design of photoprecursors from readily available building blocks (ii) Incursions into the unexplored areas of chemical space, especially via diversification of the core polyheterocyclic scaffolds.

Results
Photoprecursor sulfonamides were readily synthesized in a modular fashion as shown in Scheme 2. Well-established high yielding reactions were chosen to link the building blocks together, i.e., the likes of Suzuki coupling or effective coupling of aromatic amines with sulfonyl chlorides.Generally, three diversity inputs (the photoactive core, i.e., aminoketone, the sulfonamide tether, and the unsaturated pendant) allow for added flexibility in exploring the chemical space traversed by the resulting photoproducts.Subsequent postphotochemical modifications offer opportunities for additional diversity inputs.Irradiation of photoprecursors in DMSO with 365 nm UV LED yielded the products of [4+2] or [4+4] cycloadditions in good yields (see Table 1).
The now-ubiquitous UV LEDs @365 nm, based on Al-doped gallium nitride, with rather high radiant power are available commercially, making them the UV source of choice for large scale irradiations.LED irradiators with shorter wavelengths are becoming more accessible but their prices are still significantly higher.Additionally, the higher energy photons are more prone to causing unwanted side reactions.The 365 nm wavelength offers the optimal cost-benefit outcomes, provided that the photoprecursors absorb at this wavelength.As shown in Table 2, the precursor sulfonamides do have significant absorption at 365 nm, with molar extinction coefficients ranging from 830 to 1770 M −1 cm −1 .
Postphotochemical modifications of 12 and 13 were carried out as shown in Scheme 3 via the [4+2] (hetero-Diels-Alder) reaction of the dihydrofuran moiety in primary photoproduct (11g) and hetero-dienes generated in situ from either Meldrum's acid (green) or N,N-dimethylbarbiturate (pink) and formaldehyde, under L-proline catalysis.

91%
The now-ubiquitous UV LEDs @365 nm, based on Al-doped gallium nitride, rather high radiant power are available commercially, making them the UV sour Molecules 2023, 28, x FOR PEER REVIEW 4

91%
The now-ubiquitous UV LEDs @365 nm, based on Al-doped gallium nitride, rather high radiant power are available commercially, making them the UV sour

91%
The now-ubiquitous UV LEDs @365 nm, based on Al-doped gallium nitride, rather high radiant power are available commercially, making them the UV sour choice for large scale irradiations.LED irradiators with shorter wavelengths are becom more accessible but their prices are still significantly higher.Additionally, the highe Molecules 2023, 28, x FOR PEER REVIEW 4

91%
The now-ubiquitous UV LEDs @365 nm, based on Al-doped gallium nitride, rather high radiant power are available commercially, making them the UV sour choice for large scale irradiations.LED irradiators with shorter wavelengths are becom more accessible but their prices are still significantly higher.Additionally, the highe 91% Table 2. UV absorption of photoprecursors at 365nm.Postphotochemical modifications of 12 and 13 were carried out as shown in Scheme 3 via the [4+2] (hetero-Diels-Alder) reaction of the dihydrofuran moiety in primary photoproduct (11g) and hetero-dienes generated in situ from either Meldrum's acid (green) or N,N-dimethylbarbiturate (pink) and formaldehyde, under L-proline catalysis.Scheme 3. Postphotochemical modifications of primary photoproduct 11g resulting in complex polyheterocycles 12 and 13 (Böttcher complexity scores are shown).

Discussion
The results presented above indicate clearly that sulfonamides undergo ESIPT, generating N-sulfonyl aza-o-xylylenes capable of intramolecular cycloadditions to yield complex heterocycles possessing a fused cyclic sulfonamide moiety.Detailed photophysical Scheme 3. Postphotochemical modifications of primary photoproduct 11g resulting in complex polyheterocycles 12 and 13 (Böttcher complexity scores are shown).

Discussion
The results presented above indicate clearly that sulfonamides undergo ESIPT, generating N-sulfonyl aza-o-xylylenes capable of intramolecular cycloadditions to yield complex heterocycles possessing a fused cyclic sulfonamide moiety.Detailed photophysical study is ongoing and will be published in due course.Given that both [4+2] and [4+4] reaction topologies are realized, we hypothesize that-as in the previously reported reactions of amides-sulfonamides most likely react in their triplet state.This is a beneficial feature, as it expands the synthetic utility of these reactions giving access to higher diversity of polyheterocyclic cores in the primary photoproducts, i.e., sulfonylated quinolinols and sulfonylated azacanes.Overall, the yields of sulfonamides are generally higher than lactams derived from amidoketones.This could be attributed either to more efficient ESIPT in sulfonamides, or the higher reactivity of N-sulfonyl aza-o-xylylenes (or both).A proposed mechanistic rationale is presented in Scheme 4.
The regiochemical outcome, i.e., the competition between path a and path b in Scheme 4, is likely being controlled by the spin density in the 1,6-diradical DR1 formed as a result of the initial attack of the N-centered radical on the π-system of the hetero-dienic (i.e., furan or thiophene) pendant.In this study, photoprecursors containing thiophene produced the [4+2]-product exclusively (path a), while the reactions with furan gave both [4+2] and [4+4] products, indicating that path b was becoming increasingly more competitive with path a in the case of furan pendants.
study is ongoing and will be published in due course.Given that both [4+2] and [4+4] reaction topologies are realized, we hypothesize that-as in the previously reported reactions of amides-sulfonamides most likely react in their triplet state.This is a beneficial feature, as it expands the synthetic utility of these reactions giving access to higher diversity of polyheterocyclic cores in the primary photoproducts, i.e., sulfonylated quinolinols and sulfonylated azacanes.Overall, the yields of sulfonamides are generally higher than lactams derived from amidoketones.This could be attributed either to more efficient ESIPT in sulfonamides, or the higher reactivity of N-sulfonyl aza-o-xylylenes (or both).A proposed mechanistic rationale is presented in Scheme 4. The regiochemical outcome, i.e., the competition between path a and path b in Scheme 4, is likely being controlled by the spin density in the 1,6-diradical DR1 formed as a result of the initial attack of the N-centered radical on the π-system of the hetero-dienic (i.e., furan or thiophene) pendant.In this study, photoprecursors containing thiophene produced the [4+2]-product exclusively (path a), while the reactions with furan gave both [4+2] and [4+4] products, indicating that path b was becoming increasingly more competitive with path a in the case of furan pendants.
Product structures were determined by NMR.Given the complexity of these polyheterocyclic products, experimental NMR characterization was augmented with computational study, i.e., the experimental data were matched with spectra calculated with our machine learning-augmented DFT method, DU8ML [20,21].All structures showed convincing matches with the computed data-for example, rmsd values for 13 C NMR chemical shifts were in the 1.1-1.3ppm range and the calculated spin-spin coupling values were in keeping with the experimental observations.A typical result of DU8ML calculations of NMR parameters is shown in Table 3. Product structures were determined by NMR.Given the complexity of these polyheterocyclic products, experimental NMR characterization was augmented with computational study, i.e., the experimental data were matched with spectra calculated with our machine learning-augmented DFT method, DU8ML [20,21].All structures showed convincing matches with the computed data-for example, rmsd values for 13 C NMR chemical shifts were in the 1.1-1.3ppm range and the calculated spin-spin coupling values were in keeping with the experimental observations.A typical result of DU8ML calculations of NMR parameters is shown in Table 3.

General Information
Common solvents were purchased from Fisher Scientific (Waltham, MA, USA) and used as is.Common reagents, 2-keto amines, boronic acids, and thiols, were purchased from Sigma-Aldrich (St. Louis, MO, USA), TCI America, AK Scientific, Oakwood Chemical or AstaTech and used without additional purification.NMR spectra were recorded at 25 • C on a Bruker Avance III 500 MHz instrument (Billerica, MA, USA) in CDCl 3 (unless noted otherwise) using residual solvent peaks as an internal standard (δH 7.26 ppm, δC 77.16 ppm for CDCl 3 ; δH 2.50 ppm, δC 39.52 ppm for DMSO-d 6 ).The description of signals includes s = singlet, d = doublet, dd = doublet of doublets, t = triplet, dt = doublet of triplets, td = triplet of doublets, q = quartet, m = multiplet, br.s = broad singlet.The structural assignments were made with additional information from gCOSY, gHSQC, and gHMBC experiments.Flash column chromatography was performed using Teledyne Ultra-Pure Silica Gel (230-400 mesh) on a Teledyne Isco Combiflash Rf (Lincoln, NE, USA).The light-promoted reactions were carried out using in-house built UV LED-based illuminators equipped with seven (total power 20.3 W) LED Engin chips (18 V, 700 mA, 2.9 W, λ = 365 nm).Borosilicate glass reaction vessels were typically distanced from a light source in a range of 5-7 cm.
To a stirred solution of 2-bromobenzenesulfonyl chloride (2, 3.91 mmol), the corresponding aniline (3.91 mmol), and anhydrous pyridine (1.0 mL, 11.7 mmol) in anhydrous dichloromethane (15 mL) was stirred under an argon atmosphere.The resulting mixture was stirred at room temperature for 14 h.After completion of the reaction (the progress of the reaction was monitored by Thin layer chromatography), the reaction mixture was diluted with washed with saturated NaHCO 3 (20 mL).The reaction mixture was extracted with CH 2 Cl 2 (3 × 30 mL).The combined organic extracts were washed with water (2 × 40 mL), separated, dried over anhydrous Na 2 SO 4 , then concentrated in vacuo to give a crude yellow oil.The crude product was purified by flash chromatography on silica gel.

General Procedure for Synthesis of Aldehyde Photoprecursors (General Procedure B)
The bromide (2.0 mmol, 1.0 equiv.), the corresponding boronic acid (3.0 mmol, 1.5 equiv.),PdCl 2 (PPh 3 ) 2 (0.07 mmol, 0.04 equiv.), and K 2 CO 3 (8.0mmol, 4.0 equiv.)are suspended in DMF:H 2 O (9:1) and heated to reflux in oil bath for 14 h.Upon completion of the reaction as indicated by 1 H NMR, the mixture was diluted with EtOAc (30 mL) and washed with a saturated solution of NaHCO 3 (2 × 40 mL).Combined organic phase was washed with H 2 O (20 mL) and dried over anhydrous Na 2 SO 4 .After concentration, a crude product was used for the next oxidation reaction.To a stirred solution of the corresponding alcohol (2.5 mmol, 1.0 equiv.) in CH 2 Cl 2 (20 mL), was added MnO 2 (12.5 mmol; 5.0 equiv.) at ambient temperature, and the resulting mixture was stirred at room temperature overnight.Upon completion (the progress of the reaction was monitored by 1 H NMR), the solids were filtered off by passing the mixture through celite pad, and the pad was washed with additional 20 mL of CH 2 Cl 2 .After concentration, crude product was purified by flash chromatography on silica gel to give a desired photoprecursor.

Irradiation of Photo Precursors (General Procedure D)
A solution of photo precursor (0.30 mmol) in DMSO (80 mL, unless otherwise mentioned) was degassed by bubbling of nitrogen or argon for 45 min.The solution was irradiated with UV LED-based illuminator, seven 2.9 W (total power 20.3 W) @ 365 nm LED Engin chips.After completion of the reaction (progress of the reaction was monitored by 1 H NMR), the solvent was removed under vacuum, and a residue was subjected to purification by flash chromatography on silica gel to obtain photoproducts with moderate to good yields.

Conclusions
Aromatic sulfonamides, readily accessible via a modular "assembly" from common building blocks/diversity inputs, undergo excited state intramolecular proton transfer (ESIPT) yielding N-sulfonyl aza-o-xylylenes, which are capable of intramolecular [4+2] and [4+4] cycloadditions with tethered unsaturated pendants, most likely in the triplet manifold.The primary photoproducts are amenable to experimentally simple postphotochemical ground state reactions, offering opportunities to introduce additional diversity inputs and further grow molecular complexity as quantified by the Böttcher complexity indices.These findings expand the scope of ESIPT-based synthetic approaches and, generally, enhance the toolchest of photoassisted synthetic chemistry.
Author Contributions: Conceptualization, methodology, funding acquisition, project administration, and writing A.G.K.; investigation, data analysis, experiment implementation, S.B.All authors have read and agreed to the published version of the manuscript.